ES2226377T3 - Derivados de acido oxiimino-alcalino con actividad hipoglucemica e hipolipidemica. - Google Patents
Derivados de acido oxiimino-alcalino con actividad hipoglucemica e hipolipidemica.Info
- Publication number
- ES2226377T3 ES2226377T3 ES99918355T ES99918355T ES2226377T3 ES 2226377 T3 ES2226377 T3 ES 2226377T3 ES 99918355 T ES99918355 T ES 99918355T ES 99918355 T ES99918355 T ES 99918355T ES 2226377 T3 ES2226377 T3 ES 2226377T3
- Authority
- ES
- Spain
- Prior art keywords
- group
- carbon atoms
- ethyl acetate
- ethyl
- atoms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000002253 acid Substances 0.000 title claims description 69
- 230000000055 hyoplipidemic effect Effects 0.000 title description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 252
- -1 nitro, hydroxy Chemical group 0.000 claims abstract description 224
- 150000001875 compounds Chemical class 0.000 claims abstract description 157
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 114
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 83
- 125000004429 atom Chemical group 0.000 claims abstract description 80
- 125000001424 substituent group Chemical group 0.000 claims abstract description 65
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 56
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 56
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 56
- 125000002252 acyl group Chemical group 0.000 claims abstract description 47
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 42
- 150000002367 halogens Chemical class 0.000 claims abstract description 41
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 32
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 28
- 125000003118 aryl group Chemical group 0.000 claims abstract description 26
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 21
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 19
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 19
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 17
- 125000003302 alkenyloxy group Chemical group 0.000 claims abstract description 17
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims abstract description 17
- 125000003277 amino group Chemical group 0.000 claims abstract description 16
- 230000002265 prevention Effects 0.000 claims abstract description 16
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 15
- 125000002723 alicyclic group Chemical group 0.000 claims abstract description 15
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 15
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 10
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 10
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 9
- 125000005110 aryl thio group Chemical group 0.000 claims abstract description 9
- 239000000470 constituent Substances 0.000 claims abstract description 9
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 9
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 8
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 7
- 125000005035 acylthio group Chemical group 0.000 claims abstract description 6
- 125000005366 cycloalkylthio group Chemical group 0.000 claims abstract description 6
- 125000005368 heteroarylthio group Chemical group 0.000 claims abstract description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims abstract description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims abstract description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 125000005505 thiomorpholino group Chemical group 0.000 claims abstract description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract 8
- 150000002430 hydrocarbons Chemical class 0.000 claims description 49
- 239000003795 chemical substances by application Substances 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 239000004215 Carbon black (E152) Substances 0.000 claims description 19
- 229930195733 hydrocarbon Natural products 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 206010022489 Insulin Resistance Diseases 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- 239000008103 glucose Substances 0.000 claims description 8
- 150000002923 oximes Chemical class 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 3
- UJJXWXXGGDUKBV-BNIPGBBVSA-N (8z)-8-[[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl]methoxyimino]-8-phenyloctanoic acid Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1COC(C=C1)=CC=C1CO\N=C(\CCCCCCC(O)=O)C1=CC=CC=C1 UJJXWXXGGDUKBV-BNIPGBBVSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- RVSHTQITTSYELJ-GKPLWNPISA-N CC1=C(COC2=CC=C(CO/N=C(\CCCN)/C3=CC=CC=C3)C=C2)N=C(C2=CC=CC=C2)O1 Chemical compound CC1=C(COC2=CC=C(CO/N=C(\CCCN)/C3=CC=CC=C3)C=C2)N=C(C2=CC=CC=C2)O1 RVSHTQITTSYELJ-GKPLWNPISA-N 0.000 claims description 2
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011593 sulfur Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 543
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 184
- 239000000203 mixture Substances 0.000 description 174
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 140
- 239000013078 crystal Substances 0.000 description 131
- 235000002639 sodium chloride Nutrition 0.000 description 125
- 239000010410 layer Substances 0.000 description 123
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 116
- 239000000243 solution Substances 0.000 description 112
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 108
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 107
- 239000011541 reaction mixture Substances 0.000 description 95
- 239000011780 sodium chloride Substances 0.000 description 91
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 82
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 73
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 70
- 235000019341 magnesium sulphate Nutrition 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 68
- 239000007864 aqueous solution Substances 0.000 description 68
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- 238000000034 method Methods 0.000 description 64
- 239000003921 oil Substances 0.000 description 63
- 235000019198 oils Nutrition 0.000 description 63
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 61
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 57
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 51
- 238000003756 stirring Methods 0.000 description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 50
- 238000010898 silica gel chromatography Methods 0.000 description 45
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
- PHENPABYBHPABM-UHFFFAOYSA-N acetic acid;octane Chemical compound CC(O)=O.CCCCCCCC PHENPABYBHPABM-UHFFFAOYSA-N 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 34
- 238000010992 reflux Methods 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000002585 base Substances 0.000 description 29
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 238000001953 recrystallisation Methods 0.000 description 28
- 239000011734 sodium Substances 0.000 description 28
- 229910052708 sodium Inorganic materials 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 26
- 238000009472 formulation Methods 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- 239000013612 plasmid Substances 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 20
- 239000012230 colorless oil Substances 0.000 description 19
- 102000005962 receptors Human genes 0.000 description 19
- 108020003175 receptors Proteins 0.000 description 19
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 18
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 18
- 239000012312 sodium hydride Substances 0.000 description 18
- 229910000104 sodium hydride Inorganic materials 0.000 description 18
- 239000012634 fragment Substances 0.000 description 17
- 108010016731 PPAR gamma Proteins 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 239000001632 sodium acetate Substances 0.000 description 15
- 235000017281 sodium acetate Nutrition 0.000 description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- 229910052801 chlorine Inorganic materials 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 14
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 13
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 13
- 108010038912 Retinoid X Receptors Proteins 0.000 description 13
- 102000034527 Retinoid X Receptors Human genes 0.000 description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 239000011737 fluorine Substances 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 230000006870 function Effects 0.000 description 11
- 239000011630 iodine Substances 0.000 description 11
- 229910052740 iodine Inorganic materials 0.000 description 11
- 150000004492 retinoid derivatives Chemical class 0.000 description 11
- 239000012279 sodium borohydride Substances 0.000 description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 description 11
- 101001093899 Homo sapiens Retinoic acid receptor RXR-alpha Proteins 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- 206010006895 Cachexia Diseases 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 239000001768 carboxy methyl cellulose Substances 0.000 description 9
- 230000002708 enhancing effect Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- QJEWQQYHYXDLRZ-UHFFFAOYSA-N 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyl-1,3-oxazole Chemical compound CC=1OC(C=2C=CC=CC=2)=NC=1COC1=CC=C(CCl)C=C1 QJEWQQYHYXDLRZ-UHFFFAOYSA-N 0.000 description 8
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 8
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
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- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A61K31/425—Thiazoles
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- A61K31/425—Thiazoles
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Pain & Pain Management (AREA)
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- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Quinoline Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
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| JP12792298 | 1998-05-11 | ||
| JP12792198 | 1998-05-11 | ||
| JP12792298 | 1998-05-11 | ||
| JP12792198 | 1998-05-11 |
Publications (1)
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| ES2226377T3 true ES2226377T3 (es) | 2005-03-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| ES99918355T Expired - Lifetime ES2226377T3 (es) | 1998-05-11 | 1999-05-10 | Derivados de acido oxiimino-alcalino con actividad hipoglucemica e hipolipidemica. |
Country Status (26)
| Country | Link |
|---|---|
| US (3) | US6251926B1 (fr) |
| EP (2) | EP1428531A1 (fr) |
| JP (1) | JP2000198772A (fr) |
| KR (1) | KR100388120B1 (fr) |
| CN (1) | CN1148361C (fr) |
| AR (1) | AR029876A1 (fr) |
| AT (1) | ATE272625T1 (fr) |
| AU (1) | AU766831B2 (fr) |
| BR (1) | BR9910371A (fr) |
| CA (1) | CA2331879A1 (fr) |
| CO (1) | CO5040066A1 (fr) |
| DE (1) | DE69919156T2 (fr) |
| ES (1) | ES2226377T3 (fr) |
| HU (1) | HUP0103714A3 (fr) |
| ID (1) | ID28699A (fr) |
| IL (1) | IL139470A0 (fr) |
| LV (1) | LV12606B (fr) |
| MY (1) | MY123337A (fr) |
| NO (1) | NO317426B1 (fr) |
| NZ (1) | NZ508066A (fr) |
| PE (1) | PE20000625A1 (fr) |
| PL (1) | PL344002A1 (fr) |
| PT (1) | PT1077957E (fr) |
| RU (1) | RU2213738C2 (fr) |
| SK (1) | SK16412000A3 (fr) |
| WO (1) | WO1999058510A1 (fr) |
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| MY123337A (en) * | 1998-05-11 | 2006-05-31 | Takeda Chemical Industries Ltd | Oxyiminoalkanoic acid derivatives. |
| TWI249401B (en) * | 1999-04-14 | 2006-02-21 | Takeda Chemical Industries Ltd | Agent for improving ketosis |
| DK1206457T3 (da) * | 1999-08-27 | 2004-02-16 | Lilly Co Eli | Biaryl-oxa(thia)zolderivater og deres anvendelse som modulatorer PPAP'ER |
| DE19948126A1 (de) * | 1999-10-06 | 2001-04-12 | Max Delbrueck Centrum | Pharmazeutisches Mittel zur Behandlung von Kachexie und/oder kardiogenem Schock |
| WO2001032608A1 (fr) * | 1999-10-29 | 2001-05-10 | Takeda Chemical Industries, Ltd. | Procédé de préparation de dérivés d'acide oxyminoalcanoïque |
| AR031078A1 (es) | 1999-10-29 | 2003-09-10 | Takeda Pharmaceutical | Compuesto acido (e)-4-[4-(5-metil-2-fenil-4-oxalilmetoxi)benziloxiimino]-4-fenilbutirico cristalino, composicion farmaceutica que lo comprende y su uso para fabricar esta ultima. |
| EP1304121A4 (fr) * | 1999-11-10 | 2004-06-23 | Takeda Chemical Industries Ltd | Inhibiteurs de prise de poids |
| ES2225252T3 (es) | 1999-11-10 | 2005-03-16 | Takeda Chemical Industries, Ltd. | Compuestos n-heterociclicos de 5 miembros con actividad hipoglucemica e hipolipidemica. |
| EP1229026A4 (fr) * | 1999-11-10 | 2003-09-24 | Takeda Chemical Industries Ltd | Derives d'acide alcoxyiminoalcanoique |
| EP1277730A4 (fr) * | 2000-03-28 | 2005-03-16 | Inhibiteurs de la neovascularisation | |
| EP1310494B1 (fr) * | 2000-08-11 | 2012-01-25 | Nippon Chemiphar Co., Ltd. | ACTIVATEURS DE PPAR (delta) |
| US20060089389A1 (en) * | 2000-08-22 | 2006-04-27 | Malcolm Allison | Combination |
| PE20020617A1 (es) * | 2000-08-22 | 2002-08-05 | Novartis Ag | Composicion que comprende un antagonista del receptor at1 y un potenciador de la secrecion de insulina o un sensibilizante a la insulina |
| DE60139025D1 (de) | 2000-12-28 | 2009-07-30 | Takeda Pharmaceutical | Alkansäurederivate, verfahren zu deren herstellung und deren verwendung |
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- 1999-05-10 AT AT99918355T patent/ATE272625T1/de not_active IP Right Cessation
- 1999-05-10 KR KR10-2000-7000081A patent/KR100388120B1/ko not_active Expired - Fee Related
- 1999-05-10 IL IL13947099A patent/IL139470A0/xx unknown
- 1999-05-10 RU RU2000131183/04A patent/RU2213738C2/ru not_active IP Right Cessation
- 1999-05-10 PL PL99344002A patent/PL344002A1/xx not_active Application Discontinuation
- 1999-05-10 EP EP99918355A patent/EP1077957B1/fr not_active Expired - Lifetime
- 1999-05-10 SK SK1641-2000A patent/SK16412000A3/sk unknown
- 1999-05-10 ES ES99918355T patent/ES2226377T3/es not_active Expired - Lifetime
- 1999-05-10 PT PT99918355T patent/PT1077957E/pt unknown
- 1999-05-10 CA CA002331879A patent/CA2331879A1/fr not_active Abandoned
- 1999-05-10 WO PCT/JP1999/002407 patent/WO1999058510A1/fr not_active Ceased
- 1999-05-10 DE DE69919156T patent/DE69919156T2/de not_active Expired - Lifetime
- 1999-05-10 BR BR9910371-0A patent/BR9910371A/pt not_active IP Right Cessation
- 1999-05-10 US US09/423,854 patent/US6251926B1/en not_active Expired - Fee Related
- 1999-05-10 NZ NZ508066A patent/NZ508066A/xx unknown
- 1999-05-10 AR ARP990102190A patent/AR029876A1/es unknown
- 1999-05-10 AU AU36297/99A patent/AU766831B2/en not_active Ceased
- 1999-05-10 CN CNB998060070A patent/CN1148361C/zh not_active Expired - Fee Related
- 1999-05-10 HU HU0103714A patent/HUP0103714A3/hu unknown
- 1999-05-11 CO CO99029123A patent/CO5040066A1/es unknown
- 1999-05-11 PE PE1999000393A patent/PE20000625A1/es not_active Application Discontinuation
- 1999-12-28 JP JP11373202A patent/JP2000198772A/ja active Pending
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2000
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- 2000-11-02 NO NO20005531A patent/NO317426B1/no unknown
- 2000-11-16 US US09/714,699 patent/US6495581B1/en not_active Expired - Fee Related
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2002
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